Critical illness and sepsis are associated with significant morbidity and mortality, especially in conditions where existing therapeutic strategies remain suboptimal. Our primary aim is to leverage large repositories of granular clinical data to better understand the clinical epidemiology of critical illness, sepsis and serious infections, including defining illness burden, risk factors and clinical impact. The pathophysiology of organ dysfunction in streptococcal infection is attributed to inflammation mediated by exotoxin-mediated cytokine cascade. Clindamycin neutralizes exotoxin released by Group A Streptococcus. In a large propensity-matched cohort of patients we found that clindamycin added as an adjunct to beta lactam therapy was associated with improved survival in Group A streptococcal infection. Antibiotic overuse remains a significant problem in the critically ill and is associated with toxicity and development of antimicrobial resistance. Among critically ill patients with suspected or confirmed sepsis in a larger cohort of US hospitals, we found that use of procalcitonin significantly reduced duration of antibiotic use without worsening outcomes. We confirmed these findings in a meta-analysis of randomized controlled trials. We also describe real world use patterns of this biomarker using large an enhanced administrative dataset and are in the process of studying its performance characteristics and how providers react to procalcitonin results in patients admitted with clinical indicators of sepsis. Most estimates of sepsis incidence and mortality in existing literature are estimated using claims data. Unfortunately claims based data are subject to a variety of biases. We estimate 10-year trends in the incidence and outcome of septic shock using clinical indicators in a cohort of academic medical centers in the United States and compared it to estimates obtained using claims based data. We found that the prevalence of septic shock was rising and mortality declining over time, albeit, both less vigorously than suggested by claims based methods. In addition, we identified obesity as being associated with better outcomes in more than 50,000 patients with clinical indicators of sepsis at US hospitals. In collaboration with investigators at Harvard Medical School, we were able to study the differences in characteristics and outcomes of sepsis that originates in the community versus the hospital as well as studied variation in identifying sepsis and organ dysfunction using claims versus electronic health records. Along with the same group, we were able to assess how q-SOFA performs to identify patients with undifferentiated sepsis as well as demonstrate a simpler means of measuring organ dysfunction using electronic health records (called the e-SOFA score) that demonstrated equivalent performance characteristics than the more traditional but detailed SOFA score. Bloodstream infection is common cause of critical illness and is often a secondary complication of critical illness and its management. We determined the prevalence of ICU-related bloodstream infection in a large electronic health records-based repository and identify predictors of the same which could inform empiric antibiotic practices. Furthermore, central line-associated bloodstream infections (CLABSI) are associated with reimbursement penalties that were instituted by the Centers for Medicare and Medicaid in 2008, which, we hypothesize, has led to underreporting of CLABSI. We performed an interrupted time series analysis to study the impact of the policy on blood culture sampling, which is essential to the diagnosis of CLABSI. We are currently comparing rates of CLABSI with all cause ICU-related bloodstream infection to understand if reported declines in CLABSI are also seen in other forms of ICU-related bloodstream infection, to gauge the impact of measures to prevent CLABSI which have been intensified nationwide over the last decade.